Project Summary/Abstract Understanding the human brain and its diseases represents an enormous challenge but also an opportunity for bettering human health. Among the many remarkable attributes of the normal brain, its ability to store and retrieve information for a lifetime of learning and memories, remains one of life?s joys and mysteries. Alzheimer?s disease (AD) disrupts these cognitive functions and has enormous personal, familial, and societal costs, compounded by a disturbing absence of disease-modifying therapies despite scores of scientific theories, billions of dollars, decades of research, and hundreds of failed clinical trials. This transformative proposal will meet these challenges through studies on a newly identified molecular mechanism within the brain: neuronal gene recombination (NGR). NGR may alter individual genomes within each neuron by linking neural activity ? both normal and abnormal ? to functional DNA gene sequences within the genomes of post-mitotic neurons, doing so through a process of retro-insertion of RNA sequences to produce genomic cDNAs (gencDNAs). The resulting thousands of gene variants for just a single gene ? the AD gene APP ? offers new explanations for disease progression and the futility of AD therapeutics thus far. Three areas of study will be pursued with a team of proven investigators empowered by world class bioinformatics, Alzheimer?s disease, and neuroscience experts. First, we will define the machinery of NGR in the human brain by identifying involved genes and biochemically characterizing their function. Second, we will formally define NGR relevance to major forms of AD and therapeutics by analyses of a sufficient number of sporadic AD brains, as well as examining relationships to familial AD and Down syndrome towards identifying shared molecular etiologies. These studies will also examine a potential near-term therapy for AD by studying FDA-approved reverse transcriptase inhibitors and their impact on AD endpoints, which would be grounded in a scientific foundation based upon NGR. Third, we will use targeted and unbiased approaches to identify new NGR genes and their relationships to other brain diseases, particularly those involved with sporadic brain disorders beyond AD. These studies are the first to examine NGR, representing a new line of research without prior NIH support, with a scope not amenable to standard NIH mechanisms, towards truly transformational studies of the brain, its diseases, and the enormous challenge of AD.